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Objectives: Chronic diabetes mellitus associated with devastating complication the diabetic nephropathy, that further progress to ESRD,a major cause of morbidity and premature mortality in many countries worldwide. Accumulated evidences demonstrated that long standing hyperglycemia induced oxidative stress, inflammatory cytokines, and fibrosis plays a significant role in DN. Fisetin, a bioflavonoid, exhibited variety of promising pharmacological properties such as, anti-diabetic, antioxidant, anti-inflammatory, anti-hyperlipidemic ,and anti-carcinogenics. Hence, the present study was hypothesized to investigate, the effect of fisetin on streptozotocin-induced diabetic nephropathy in rats. Materials and Methods: Sprague Dawley rats were divided into 6 groups (n=6) as normal control, diabetic control (vehicle), Glimepiride (0.5 mg/kg, orally) and Fisetin treatment (2.5, 5 and 10 mg/kg, orally) groups. After the confirmation of diabetes, vehicle/drug treatments were started and continued for 6 weeks. Serum glucose, body weight, were measured on weekly basis.Thereafter, on the last day of treatment protocol, ie 42 day, serum insulin, HbA1c in blood, lipid parameters, creatinine, albumin and urea in serum and in urine creatinine excretion, albumin were measured along with urine volume and creatinine clearance. In addition, weight of kidney and histopathological studies were carried out. Results: Fisetin treatment significantly attenuated reduction in body weight. Also, it significantly decreased the blood glucose level, ameliorate lipid profile and HbA1c (p<0.05) value, but serum insulin level were not much influenced. It also increased albumin in serum, decreased serum urea and creatinine and in urine, it reduced the urine volume, albumin with marked improvement in creatinine excretion and creatinine clearance. Further, the fisetin (10mg/kg) treatment attenuated oxidative stress and cytokines TNF-α (p<0.01), IL-1β (p<0.01), and IL-6 (p<0.05) level in kidney tissue along with amelioration of histopathological alterations compared to diabetic control rats. The standard drug, glimepiride also exhibited similar antidiabetic effect without much influence on oxidative stress, albumin in urine, and cytokine levels. Conclusions: The results indicated that fisetin ameliorated diabetic nephropathy through its antidiabetic and antioxidant effect which may be attributed to inhibition of downward pathway of glycemia induced oxidative stress, inflammation and necroptosis of renal tissue.